Recent human clinical trials have demonstrated a cancer-chemopreventive effect of dietary selenium, and several additional trials are underway. However, the molecular basis for chemoprevention by this essential trace element remains unknown. Furthermore, it is not clear why dietary supplementation with selenium prevents some cancers, such as those of the prostate, colon, and lung, but is ineffective against others, such as melanoma. On the basis of preliminary studies, it is suggested that cancers can be divided into at least 2 major types on the basis of regulation of selenoprotein expression: Type I cancers are characterized by a reduced expression of selenoproteins and a consequent disruption of redox homeostasis compared with corresponding normal tissue, whereas selenoprotein abundance and cellular redox parameters are unaffected in Type II cancers. Selenium supplementation within normal dietary levels is known to increase both selenoprotein expression and antioxidant defenses. It is proposed that: (1) antioxidant selenoproteins, rather than low molecular weight selenium-containing oxidants, contribute to the chemopreventive effect of selenium, and that (2) selenium is effective against cancers of Type I but not against those of Type II. These hypotheses will be addressed with the use of transgenic mice that overexpress either transforming growth factor a (and develop Type I liver cancer) or the c-Myc proto-oncogene (and develop Type II liver cancer). These animals will be maintained on selenium-deficient, selenium-sufficient, or selenium-enriched diets, after which the incidence, grade, multiplicity, and size of tumors will be determined and correlated with selenium-induced changes in selenoprotein expression and markers of redox homeostasis. In addition, DNA, microarray technology will be applied to define the pattern of gene expression induced by selenium deficiency or supplementation in normal and cancer tissue from transgenic mice. These approaches should yield insight into the mechanism of the anticancer effect of selenium and may lead to the identification of human cancers most susceptible to selenium chemoprevention.